Journal of Allergy and Clinical Immunology: Global (Aug 2024)

A highly selective KIT inhibitor MOD000001 suppresses IgE-mediated mast cell activation

  • Yuki Nakamura, PhD,
  • Takeo Urakami, PhD,
  • Kayoko Ishimaru,
  • Nguyen Quoc Vuong Tran, PhD,
  • Takafumi Shimizu, MS,
  • William Sinko, PhD,
  • Taisuke Takahashi, PhD,
  • Sivapriya Marappan, PhD,
  • Kishore Narayanan, PhD,
  • Ramulu Poddutoori, PhD,
  • Yoh Terada, PhD,
  • Atsuhito Nakao, MD, PhD

Journal volume & issue
Vol. 3, no. 3
p. 100249

Abstract

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Background: The KIT receptor tyrosine kinase and its ligand, stem cell factor (SCF), control proliferation and survival of mast cells. Thus, targeting KIT signaling may show promise for the treatment of allergic diseases involving mast cells. Recently, we discovered a new compound, MOD000001, as a potential small-molecule KIT kinase inhibitor by using an in silico approach. Objective: We sought to determine whether MOD000001 is highly selective to KIT, inhibits KIT signaling in mast cells, and affects IgE-mediated mast cell activation. Methods: The interaction of MOD000001 with 468 human kinases and its inhibitory activity against KIT were profiled and evaluated by using KINOMEscan (Discover X/Eurofins Corporation, Fremont, Calif) and cell-free kinase assays, respectively. The effects of MOD000001 on SCF-dependent signaling were examined by using primary mouse and human mast cells. The effects of MOD000001 on SCF-induced degranulation and passive cutaneous anaphylaxis reaction were examined in mice. Results: MOD000001 interacted with KIT and inhibited KIT kinase activity with high selectivity. MOD000001 suppressed SCF-induced KIT signaling in mouse and human mast cells and in mice. Passive cutaneous anaphylaxis reaction was suppressed in mice treated with MOD000001 both for a short-term (1 week) and for a long-term (7 weeks). Mice treated with MOD000001 for a long-term, but not for a short-term, showed skin mast cell reduction. Conclusions: MOD000001 is a highly selective KIT inhibitor that can suppress IgE-mediated mast cell activation in vivo. MOD000001 may do so by reducing tissue mast cell numbers or by other unknown mechanisms. The findings suggest potential benefits of MOD000001 for allergic diseases involving IgE-mediated mast cell activation.

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